Bloody stool in breast-fed infants Cow's milk protein allergy is still possible !!! (via maternal exposure to milk at lactation)

1. ORIGINAL ARTICLE
Allergic Colitis in Infants Related to Cow’s
Milk: Clinical Characteristics, Pathologic
Changes, and Immunologic Findings
Man-Chun Yu a
, Chia-Lun Tsai b
, Yao-Jong Yang a
, Sing-San Yang a
,
Li-Hui Wang a
, Chung-Ta Lee c
, Ren-Long Jan d,e
, Jiu-Yao Wang a,b,d,
*
a
Division of Allergy and Clinical Immunology, Department of Pediatrics, National Cheng Kung University Hospital,
Tainan, Taiwan
b
Institute of Microbiology and Immunology, National Cheng Kung University Hospital, Tainan, Taiwan
c
Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan
d
Institute of Clinical Medicine, College of Medicine, National Cheng Kung University Hospital, Tainan, Taiwan
e
Department of Pediatrics, Chi-Mei Medical Center, Liou-Yin Campus, Tainan, Taiwan
Received Aug 18, 2011; received in revised form Jan 19, 2012; accepted Jun 5, 2012
Key Words
allergic colitis;
IgE;
IgG subclass;
milk protein allergy;
skin prick test
Background: Allergic colitis (AC) is an inflammatory condition characterized by eosinophils
infiltrating the colonic wall. It can be a benign and/or severe illness among gastrointestinal
diseases in infants.
Methods: We report five infants who, since January 2009, in whom AC under fibrotic endo-
scopic examinations has been diagnosed. The criterion for histopathologic diagnosis of AC in
this study was five or more eosinophils per high-power field. Patients’ clinical symptoms, path-
ologic findings, and immunologic studies, such as specific antibodies against component of
cow’s milk protein, were compared with those of allergic children without AC and those of non-
atopic control children.
Results: Histopathologic examinations of biopsy specimens revealed acute inflammation with
characteristic eosinophilic infiltration of lamina propria (5e15 eosinophils per high-power
field) in all five patients. They all had strongly positive skin prick tests against milk protein,
which were not correlated with in vitro allergen-specific immunoglobulin (Ig) E levels. In
contrast, there were significantly higher levels of IgE antibodies, and lower specific IgG4 and
IgA levels to components and whole milk proteins in AC, as compared to control children
without AC.
* Corresponding author. Division of Allergy and Clinical Immunology, Department of Pediatrics, College of Medicine, National Cheng Kung
University Hospital, Number 138, Sheng-Li Road, Tainan, Taiwan.
E-mail address: a122@mail.ncku.edu.tw (J.-Y. Wang).
1875-9572/$36 Copyright ª 2012, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rights reserved.
http://dx.doi.org/10.1016/j.pedneo.2012.11.006
Available online at www.sciencedirect.com
journal homepage: http://www.pediatr-neonatol.com
Pediatrics and Neonatology (2013) 54, 49e55

2. Conclusion: Endoscopic biopsy specimens of intestine confirm the diagnosis of AC. However,
allergen skin prick test and IgE antibody to milk protein components also provide helpful diag-
nostic tools for this rare disease in children.
Copyright ª 2012, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rights
reserved.
1. Introduction
Cow’s milk allergy was considered an infrequent disease
until the 1980s, when an increasing frequency of this
disease was noted, possibly due to a decrease in breast-
feeding and a more frequent use of cow’s milk-based infant
formula feeding.1,2
During the past few decades, cow’s milk
allergy has become the most common food allergy in early
childhood in Taiwan as well as in other parts of the world.3,4
However, much controversy still exists, possibly due to
a lack of agreement on standard terminology and reliable
diagnostic tests.5
In addition to the well-recognized, immediate-onset
immunoglobulin (Ig) E-mediated allergies, there is
increasing evidence to support the role of cow’s milk
protein-induced allergy in a spectrum of delayed-onset
disorders ranging from gastrointestinal symptoms to chronic
eczema and respiratory disorders.6
Among the food-allergic
disorders affecting the gastrointestinal tract, there are
myriad clinical manifestations (vomiting, diarrhea, growth
failure, abdominal pain) and a broad range of severity and
chronicity. Many of these disorders [e.g., cow’s milk-
induced proctocolitis, enterocolitis syndrome, gastro-
esophageal reflux, eosinophilic esophagitis (EE), and
eosinophilic colitis (EC)] remain less well defined and
frequently overlap.7e9
Allergic colitis (AC) or proctocolitis induced in infants by
cow’s milk and/or soy protein, although rare, has been
recognized for decades.9
This broad spectrum of symptoms
typically begins in the first few months of life, usually
presenting with colic-like symptoms and visible fresh blood
mixed with mucus in the stool, but otherwise thriving, to
the status in association with failure to thrive and possibly
progressing to acidemia and shock.10
EC poses numerous
diagnostic and therapeutic challenges. In this study we
collected five infants with AC under fibrotic endoscopic
examinations, in whom the condition was diagnosed since
January 2009. Their clinical symptoms and pathologic
findings were reported, and immunologic studies, such as
specific antibodies (IgE, IgA, IgG1, and IgG4) against
components of cow’s milk protein were compared with
those of allergic children without AC and those of nonatopic
control children.
2. Materials and Methods
2.1. Study participants
We collected five infants who were admitted to our pedi-
atric ward due to anemia, blood-tinged stools, and/or
hypoalbuminemia. The diagnosis of AC was confirmed by
obtaining intestinal biopsy specimens during fibroblastic
endoscopic examination. The criterion for histopathologic
diagnosis of AC in this study was five or more eosinophils per
high-power field.11
Follow-up laboratory examinations and
immunologic studies for cow’s milk allergy in these patients
were performed with the consent of their legal guardians.
We also enrolled three groups of study populations, chil-
dren with specific IgE antibody against cow’s milk allergen
and clinical symptoms related to cow’s milk allergy (Group
I), children with detectable IgE antibody levels against
cow’s milk but no clinical symptoms of cow’s milk allergy
(Group II), children without cow’s milk allergy symptoms
nor with IgE antibodies against cow’s milk (Group III), five
patients in each group, for the comparisons of their specific
antibodies against components of cow’s milk protein. The
ethics committee of National Cheng Kung University
Hospital approved this study project.
2.2. Skin prick tests
Skin prick tests with cow’s milk extract and egg white
allergens (Allermed, Mountain View, CA, USA) were per-
formed in all study populations. Histamine (10 mg/mL) and
physiologic saline served as positive and negative control
agents, respectively. A wheal of 3 mm or larger was
regarded as positive, according to European Academy of
Allergy Asthma and Clinical Immunology (EAACI) guide-
lines.11
Skin prick tests were always performed by the same
experienced allergist (Y.M.C.). The reader of the prick test
result was blind to the results of the challenge test.
2.3. Specific IgE and IgG subclass antibody against
components of cow’s milk
The determination of IgE, IgA, IgG1, and IgG4 antibodies to
whey protein (W-1500 Sigma-Aldrich, San Louise, MO, USA),
a-casein (C6780, Sigma-Aldrich), b-lactoglobulin (L3908,
Sigma-Aldrich), regular infant formula (whole cow’s milk),
and hydrolyzed milk was performed with a sensitive
enzyme-linked immunosorbent assay (ELISA) method, as
described in detail by Oldeaus et al.12
Briefly, 96-well
microtiter plates (Life Technologies AB, Taby, Sweden)
were coated with components of cow’s milk proteins. Free-
binding sites were blocked with bovine serum albumin.
Human serum samples or buffer without added serum
(blanks) were added to duplicate wells, and then mono-
clonal antibodies to human IgE (A80-108P, Bethyl Labora-
tories, Montgomery, TX, USA), antihuman IgA (A0295, clone
GA-112, Sigma-Aldrich), antihuman IgG1 (B6775, clone 8c/
6-39, Sigma-Aldrich), and antihuman IgG4 (B3648, clone HP-
6025, Sigma-Aldrich) were added. After incubation and
extensive washing with washing buffer, alkaline-
50 M.-C. Yu et al

3. phosphatase-conjugated rabbit antimouse IgG was added,
and p-nitrophenyl phosphate was used as a substrate to
develop datable color. The optical density (OD) was read at
405 nm. Values were expressed as arbitrary units (AU)
deduced from the OD of the reference serum curve, after
subtracting the blanks. A coefficient of variation (CV) less
than 15% was accepted for duplicate samples. Intra-assay
CVs were less than 5%. Interassay CVs were less than 15%.
Circulating IgE antibodies to whole cow’s milk, bovine b-
lactoglobulin, bovine a-casein, and whey protein were also
analyzed and confirmed with high-sensitivity protocol for
the CAP-RAST system (Pharmacia, Uppsala, Sweden).
2.4. Statistics
Because the results were not normally distributed,
nonparametric tests were used. Comparisons between
groups with continuous variables were analyzed with the
Kruskal-Wallis test. If there was an overall significant
difference, pairwise comparisons between groups were
made with the Mann-Whitney U-test. A p value <0.05 was
considered significant in all tests.
3. Results
3.1. Summary of clinical presentation of studied
patients
Table 1 summarizes basic information of the five young
infants with ACs. There were three female and two male
infants, all younger than 24 months (age 1e22 months),
who were admitted to our pediatric ward during January
2009 to December 2010 due to the major complaint of
blood-tinged stools. Complete blood count of these
patients showed that total white blood cell counts were
normal, with mild elevation of eosinophil differential
counts (0e4%). In contrast, marked anemia, iron deficiency,
and hypoalbuminemia were noted in three of the five
patients. Laboratory examinations of hepatic enzymes,
blood urea nitrogen, and creatinine all were within normal
ranges. Regarding their feeding histories, only two patients
(Cases A and C) were fed with regular infant formula; the
other three were solely breastfed from 1 to 19 months. The
maternal daily diets of these three breastfed infants
consumed regular amounts of milk and eggs (i.e., 1 cup of
cow’s milk and 1 egg per day).
3.2. Endoscopic and histopathologic examinations
To identify the cause of lower gastrointestinal bleeding, all
patients underwent rectosigmoidoscopy performed with
a flexible endoscope under general anesthesia. The evalu-
ation was made and confirmed by microscopic examination
of biopsy samples. Focal mucosal erythema, ecchymoses,
and aphthous ulcerations were the most common endo-
scopic findings (Figure 1). Histopathologic examinations of
biopsy specimens revealed acute inflammation with char-
acteristic eosinophilic infiltration of lamina propria (5e15
eosinophils per high-power field, normal value below 5
eosinophils per high-power field), occasionally in associa-
tion with lymphoid nodules (Table 2). Diseases that also
have colonic tissue eosinophils, such as those caused by
Table 1 Basic information of infants with eosinophilic
enterocolitis.
Cases A B C D E
Age (month of age) 11 9 22 1 22
Sex F M F F M
White cell count
(K/cmm)
11.0 6 10.5 11.9 7.2
Hb (g/dL) 6.5 7.7 4.1 15.4 12.9
Eosinophils (%) 4 3 2 0 3
Serum albumin/total
protein (g/dL)
1.2/2.6 ND 1.8/2.7 ND ND
BUN (mg/dL) 12 6 13 13 11
Creatinine (mg/dL) 0.32 0.29 0.2 0.88 0.31
AST/ALT (U/L) 31/19 61/29 40/15 72/17 d
Breastfeeding
history (mo)
N Y (9) N Y (1) Y(19)
ALT Z alanine aminotransferase; AST Z aspartate amino-
transferase; BUN Z blood urea nitrogen; Hb Z hemoglobin;
ND Z not determined.
Figure 1 Endoscopic examination of infants with eosinophilic colitis. Focal mucosal erythema, ecchymoses, and aphthous
ulcerations (A), as well as nodule-like lymph node hyperplasia (B) were common features.
Allergic colitis in infants 51

4. parasite or drug-induced, inflammatory bowel disease, and
vascular connective tissue disorder, were ruled out because
of the patients’ young age and clinical histories.
3.3. Skin prick tests and specific IgE antibodies
against milk proteins
All the patients underwent skin prick tests for total and
specific (CAPÒ
) IgE levels to cow’s milk and egg white.
Table 3 summarizes the results, which show that Cases A
and C had higher total IgE than the range in those of the
same age in the general population (<25 IU), as well as
higher specific IgE antibody levels against cow’s milk.
Nonetheless, all patients showed strong reactions to cow’s
milk by the skin prick test (Figure 2); these results were not
correlated to their respective levels of specific IgE of cow’s
milk.
3.4. Specific antibodies to components of milk
protein
To further characterize the allergic reaction due to milk
proteins in our study patients, we coated milk protein, a-
casein, b-lactoglobulin, whey, and extensively hydrolyzed
cow’s milk on ELISA plates and incubated them with patient
sera, detected with labeled antihuman IgE, IgA, IgG1, and
IgG4 antibody. Table 4 shows the results of the specific
antibodies against milk protein components in these five
patients. There were high levels of specific IgE against
components of milk protein, even to extensively hydrolyzed
milk. In contrast, IgG4 subclass antibodies against
components of milk protein were very low in these patients
with AC.
To investigate the immunologic characteristics of these
five infants with AC, we collected sera from children with
antimilk IgE antibody and milk allergic symptoms (Group I),
children with antimilk IgE antibody but no milk allergy
history (Group II), and children without antimilk IgE anti-
body nor with milk allergic symptoms (Group III). Figure 3
reveals specific IgE, IgA, IgG1, and IgG4 antibodies against
components or whole milk proteins among these four
groups. There were significantly higher levels of IgE anti-
bodies to components and whole milk proteins compared
with Groups II and III (p < 0.05), respectively. In contrast,
there were significantly lower specific IgG4 and IgA levels to
whole milk protein compared with the other three groups
(p < 0.05). It is interesting to note that there were also
specific IgE, IgG1, and IgA antibodies detectable against
hydrolyzed milk, but not in the other three groups.
4. Discussion
According to a recently published article,13
eosinophilic
gastrointestinal disorders (EGID) may be categorized as EE,
eosinophilic gastroenteritis, and EC. The clinical presenta-
tion of EGID depends on the segment of the gastrointestinal
tract affected, the depth to which the eosinophils infiltrate
the intestinal wall, and the local tissue response. The
diagnosis of EE is made when esophageal biopsies show an
increased number of eosinophils (15 per high-power field).
EC can present primarily as a separate entity or a secondary
manifestation of other diseases affecting the gut. The
diagnosis of AC is more challenging because it lacks a clear
definition. No guidelines exist. It remains, therefore,
a diagnosis of exclusion. EC or enterocolitis is an uncommon
disease in children14
and is especially rare in newborn
Table 2 Histologic examinations of biopsy specimens.
Case Pathologic findings H&E stain
(100Â)
Eosinophils infiltration/
high-power field
A Section of the small intestine shows mildly increased mature eosinophils
infiltrating in the lamina propria.
9.5
B Chronic inflammatory cell infiltration in duodenal mucosal tissue. 12
C Nonspecific lymphocytic infiltration in the colonic mucosa. 5
D Colonic mucosa with marked edema and lymphoplasmic infiltration. There
are many but not heavy eosinophils in the lamina propria.
9.7
E Nonspecific lymphocytic infiltration in the intestinal mucosa. 15
H&E Z hematoxylin and eosin stain.
Table 3 Total IgE, allergen-specific IgE, and skin prick tests (wheal/flare after 30 minutes).
Cases Total IgE
(IU/mL)
Milk SPT(mm) Antimilk
IgE (AU)
Egg white SPT (mm) Anti-egg white
IgE (AU)
A 67.1 (10Â15)/(20Â25) 0.42 (10Â10)/(30Â30) 1.19
B 3.05 (6Â5)/(20Â15) 0.021 (3Â3)/(3Â3) 0.21
C 25.4 (10Â10)/(20Â15) 0.651 (3Â3)/(3Â3) 0.28
D 3.27 (8Â10)/(23Â25) 0.02 (9Â10)/(20Â25) 0.02
E 160 (10Â13)/(20Â23) 0.021 (10Â12)/(15Â20) 0.21
AU Z arbitrary units; SPT Z skin prick test.
52 M.-C. Yu et al

5. infants.15
Its uncertain immunopathogenesis may be char-
acterized by infiltration of the intestinal walls with eosin-
ophils, absence of vasculitis, and peripheral blood
eosinophilia.16e18
Although EC in infants is usually a short-
lived disorder that responds to the exclusion of cow’s
milk protein from the diet,16
EC can be associated with
a variety of chronic and debilitating gastrointestinal
symptoms19
and severe illness that leads to ileal perfora-
tion and intestinal intussusceptions.20,21
In this report, AC was diagnosed in five infants with
similar findings: the colon was inflamed on visual inspec-
tion, and on histopathologic examinations, the lamina
propria of rectal mucosa were infiltrated with
eosinophils.22
Although their symptoms and signs were
compatible to those in other reports of EC in children,
including nausea, vomiting, abdominal pain, gastrointes-
tinal bleeding, diarrhea, weight loss, and ascites, in
contrast to the previously common notion that EC in infants
is usually a non-IgEemediated disease,23
we found there
were strong reactions to cow’s milk protein of skin prick
tests in all five patients. Moreover, only two patients (Cases
A and C) had sera antimilk IgE levels above 0.05 AU that
could be considered IgE-mediated milk allergic syndrome,
whereas with the skin prick test to milk allergen, these five
patients with AC all revealed strongly positive results (Table
3). These inconsistent results between allergen skin prick
tests and in vitro allergen-specific IgE antibodies were not
infrequent in food protein-induced EC.24
Although conditions such as milk protein-induced proc-
tocolitis, enteropathy, and eosinophilic gastro-
enteropathies may all present with overlapping clinical
features,25
in our patients with milk protein-induced EC, it
is interesting to note that there were three patients (Cases
B, D, and E) for whom breastfeeding was exclusive without
any ingestion of infant formula starting from birth (Table
1). Berezin et al,26
in an attempt to define more precisely
the clinical characteristics and course of milk protein
intolerance, studied 22 infants (age 2e16 weeks), all of
whom presented with the presence of gross blood in the
stool hematochezia. Of these patients, 11 were receiving
cow’s milk, four were on soy protein, two were on cow’s
milk and soy milk, and five were breastfed. All mothers of
breastfed infants ingested whole cow’s milk during
Figure 2 Skin prick tests with normal saline, cow’s milk, and
egg allergen.
Table 4 Specific antibodies against components of milk protein.
Case/antibodies Cow’s milk Hydrolyzed
milk protein
a-casein b-lactoglobulin Whey protein
IgE (OD)
1 1.49 0.55 1.71 0.62 1.27
2 0.08 0.03 ND 0.06 0.01
3 0.62 ND 0.33 0.38 0.37
4 1.14 0.46 1.08 0.49 0.50
5 0.92 0.47 0.63 0.99 0.83
IgA (OD)
1 ND 1.71 0.53 0.28 1.27
2 0.28 0.06 0.93 0.08 0.32
3 3.08 0.10 2.05 0.25 2.00
4 ND 1.08 0.14 0.06 0.50
5 ND 0.63 0.22 0.33 0.83
IgG1 (OD)
1 ND 0.62 0.72 0.19 0.55
2 0.37 0.27 0.13 0.15 0.22
3 0.97 0.11 2.33 0.66 0.70
4 ND 0.49 0.69 0.15 0.46
5 ND 0.99 0.28 0.24 0.47
IgG4 (OD)
1 0.02 ND 2.72 0.14 1.53
2 ND ND ND ND ND
3 2.67 ND 1.06 2.88 2.48
4 ND ND 0.37 0.02 1.14
5 ND ND 2.67 2.07 0.92
Ig Z immunoglobulin; ND Z not determined; OD Z optical density.
Allergic colitis in infants 53

6. lactation. Rectal bleeding stopped in 19 of 22 infants within
1 week of transfer to a protein hydrolysate formula.
Therefore, the cow’s milk protein might have been present
in the breast milk, which could sensitize and trigger milk
protein-induced AC in these infants.
To our knowledge, there have not been any previous
reports regarding the role of serum total IgE, IgA, IgG
subclass antibody, and allergen-specific antibodies in milk
protein-induced AC. In Table 4 and Figure 3, we show that
there were significantly higher levels of IgE antibodies, and
lower specific IgG4 and IgA levels to components and whole
milk proteins in AC as compared to those in control patients
without AC. Previously, Host et al27
measured prospectively
the development of serum IgE, IgG, IgG subclass, and IgE
antibodies to dietary cow’s milk proteins from birth (cord
blood) to 12 months of age in 39 infants with cow’s milk
protein allergy. They found determination of IgG antibody
and IgG subclass antibodies (IgG1 and IgG4) to bovine
lactoglobulin and bovine whey in cord blood appeared
unable to discern infants at high risk of development of
cow’s milk protein allergy. However, infants with persistent
cow’s milk protein allergy have an increased antibody
response of specific IgE and IgG subclasses (IgG1 and IgG4)
to cow’s milk protein exposure. Further study also
confirmed that clinical course and prognosis of cow’s milk
allergy were dependent on milk-specific IgE status in
infants.28
In summary, for an uncommon disease of milk
protein-induced AC in infants, signs and symptoms of
blood-tinged stools and anemia that rule out infection
should alert clinicians of the possibility of milk protein
allergy.29
Although endoscopic biopsy specimens of the
intestine may confirm the diagnosis of AC, allergen skin
prick test and IgE antibody to milk protein components
also provide helpful diagnostic tools for this rare disease
in children.
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